Novel Myocilin Mutation in a Chinese Family With Juvenile-Onset Open-Angle Glaucoma

Objective

To search for the genetic cause of juvenile-onset open-angle glaucoma (JOAG) in a Chinese family.

Methods

In a 3-generation glaucoma family affected with JOAG or ocular hypertension, we screened myocilin (MYOC) and optineurin (OPTN) for mutations and investigated apolipoprotein E (APOE) polymorphisms in 6 family members, 2 of them patients with JOAG, 2 patients with ocular hypertension, and 2 patients who were asymptomatic. Normal controls included 200 unrelated Chinese subjects. The COS-7 cell line was transfected with expression vectors encoding wild-type or mutatedMYOCcomplementary DNA. Cellular and secreted MYOC proteins were characterized by Western blotting.

Results

One missenseMYOCmutation, 734G>A: Cys245Tyr, was identified. It occurred in all 4 family members afflicted with JOAG or ocular hypertension but not in asymptomatic family members. NoOPTNvariations were observed.APOEpolymorphism frequencies were similar to those for controls. The Cys245TyrMYOCmutation cosegregated with the disorder within the family. It was absent in the 200 control subjects. The Cys245Tyr mutant MYOC protein formed homomultimeric complexes that migrated at molecular weights larger than their wild-type counterparts. These mutant complexes remained sequestered intracellularly in COS-7 cells.

Conclusions

The Cys245TyrMYOCmutation was the genetic cause of JOAG in this Chinese family. This mutation may alter covalent bonds that formed between MYOC cysteines.

Clinical Relevance

Genetic tests ofMYOCmutations may be beneficial to predict new cases of the disease in families with JOAG.